Bismuth-based nanoparticles as theranostic agents for x-ray Computed Tomography (CT) and radiation therapy

Algethami, M 2018, Bismuth-based nanoparticles as theranostic agents for x-ray Computed Tomography (CT) and radiation therapy, Doctor of Philosophy (PhD), Health and Biomedical Sciences, RMIT University.

Document type: Thesis
Collection: Theses

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Title Bismuth-based nanoparticles as theranostic agents for x-ray Computed Tomography (CT) and radiation therapy
Author(s) Algethami, M
Year 2018
Abstract Ideal radiotherapy treatment involves the delivery of a pre-set dose of ionising radiations to a well specified target by radiologic imaging techniques. Conforming the dose to the target is crucial as ionising radiation causes damage to healthy tissues. Rapid imaging and dose delivery modalities, which have also been developed, have brought a great improvement in accuracy of targeted cancer treatments. However, current diagnostic and treatment procedures are still limited by insufficient accuracy in terms of the radiobiology of radiotherapy. Hence, a major area of endeavour is improving their accuracy and therapeutic effects. Recently, research has focused primarily on attempting to radio-sensitise targets. This process involves inclusion of high atomic number (Z) materials into targets prior to irradiation. To increase efficiency of this process, nanoparticles (NPs) consisting of high Z elements are used. Incorporation of these materials with medical imaging devices such as X-ray computed tomography (CT) scans leads to improved disease characterisation and monitoring of response to therapy. Moreover, nanoparticles can enhance dose effects in external beam radiotherapy. The rationale behind this work was to develop and characterise NPs and incorporate them into the processes employed by current diagnostic CT imaging devices in order to enhance sensitivity and increase the chance of identifying disease at a time when the patient can receive a positive prognosis.

This enhancement is also important in advancing towards eliminating the need for invasive biopsies, which is currently the most accurate diagnostic method for cancer detection and therapy follow up. In addition, the same NPs can be used as dose enhancement agents to improve radiotherapy effects on cancerous tissues whilst minimising effects on healthy tissues. Therefore, this thesis had the two major aims: to use bismuth-based NPs as dual-function agents for cancer; diagnostic as well as therapeutic. Using a single system to enhance detection as well as boost therapeutic efficacy leads to the promising platform called “theranostics”. Optimisation of the diagnostic and therapeutic strategies simultaneously enhances cancer control and increases patient’s survival rates. Contrast agent studies were conducted using phantoms with CT scanners, while radiation dose enhancement was carried out using biological cell survival assays and two radiotherapy techniques; superficial radiotherapy (SXRT) (kV) and megavoltage (deep) (MV) therapy with a linear accelerator (LINAC). The results of the study provided evidence that bismuth (Bi) and its compounds (bismuth sulfide (Bi2S3) and bismuth oxyiodide (BiOI) NPs) can be synthesised and surface-modified using suitable biocompatible methods. Attention was also given also to nanoparticle-surface coating effects in optimising long term stability. Furthermore, the NPs were characterised using transmission electron microscopy (TEM), X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FT-IR) and Zeta potential measurements in order to confirm nanoparticle size, compositions and surface modifications.

It was established that bismuth-based NPs can be produced in small and well-defined sizes and are stable in water for a long period of time. Initially, experiments investigated the feasibility of employing high-Z Bi2S3-NPs as a contrast agent for CT compared to conventional contrast media (CM). An extended study determined the optimal clinical tube potentials for visualisation of Bi-based NPs with respect to iodinated CM. Results showed particular promise for maximising contrast enhancement across the studied range of 80 to 140 kilovoltage (kV). These results were supported by National Institute of Standards and Technology (NIST) mass attenuation data. A second, novel study was conducted to determine the benefit of the K-edge value for Bi and iodine (I), using bismuth oxyiodide (BiOI) NPs to enhance subject contrast in dual-energy (DE-CT) and spectral (MARS) CT imaging. Both CT scanners revealed the superiority of BiOI-NPs over the conventional iodinated contrast agents. A second series of studies was conducted to develop cell culture-related protocols to measure the response of different cell lines exposed to X-ray radiotherapy beams with energies in kVp and MV as well as to measure the effect of NPs containing high Z on the radiation responses. The first study was carried out to investigate and compare the effect of Bi2S3 and gold (Au)-NPs on the radiation response of mouse PC3 prostate and B16 melanoma cells. Equimolar concentrations of both Au and Bi2S3-NPs displayed equal dose enhancement with B16 cells, while the latter provided higher values with PC3 cells. At equimolar concentrations there are less Bi atoms compared to Au in their respective NPs. Both NPs at comparable concentrations (0.5-1 mM) elicited similar cytotoxicity in PC3 cells.

This study demonstrates that the less expensive Bi2S3-NPs are a viable alternative to Au-NPs as a dose-enhancing agent in clinical applications. The second study investigated the cytotoxicity of Bi- and Bi2S3-NPs towards two human cell lines, A549 (lung adenocarcinoma epithelial) and DU145 (prostate carcinoma). Results revealed that Bi-NPs at comparable concentrations to Bi2S3- NPs (0.5-1 mM) caused higher cytotoxicity in both cell lines. The presence of both NPs led to decreasing the surviving fraction of cells when NPs were combined together with X-ray irradiation, compared to the control (irradiation alone). Cells irradiated with kVp energies showed the greatest radiosensitisation value compared to MV energies. Results also demonstrated that Bi-NPs generated a greater dose enhancement effect than Bi2S3-NPs in irradiated cells. The maximum Dose Enhancement Factor (DEF) obtained at the lower energy kV range for cells treated with Bi-NPs (0.25 mM) was 2.29 in A549 cells and 1.56 in DU145 cells, compared to the DEF values of 1.41 in A549 cells and 1.63 in DU145 cells when cells were treated with higher concentrations (1mM) of Bi2S3-NPs. Lower radiation dose enhancement was observed when using a high energy MV beam, with higher DEF values for Bi-NPs (0.25 mM) treatment (1.26 in A549 cells and 1.23 in DU145 cells) as compared to DEF values with similar concentrations of Bi2S3-NPs (1.09 in A549 cells and 1.07 in DU145 cells). Using a linear quadratic model to analyse the radiobiological effect of the dose enhancement by NPs it were found that there was systematic changes of the alpha (α) value which increased by treating with the NPs, while there were very small changes for the beta (β) value.
Degree Doctor of Philosophy (PhD)
Institution RMIT University
School, Department or Centre Health and Biomedical Sciences
Subjects Medical Physics
Keyword(s) Bismuth NPs
Bi2S3 NPs
Contrast agents
Dose enhancement agents
Theranostic agents
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Created: Fri, 27 Apr 2018, 13:38:40 EST by Denise Paciocco
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